Phosphorus binder

ABSTRACT

A calcium formate composition for oral administration to an individual for the purpose of inhibiting gastrointestinal absorption of phosphorous is disclosed. A method of inhibiting gastrointestinal absorption of phosphorous, comprising administering orally the composition, preferably close in time to food and beverage consumption is also disclosed.

BACKGROUND OF THE INVENTION

Phosphorus retention plays a major role in chronic renal failure in thedevelopment of both secondary hyperparathyroidism and osteodystrophy.Bricker, N., S. et al., Archives of Internal Medicine 123:543-553(1969); Rubini, M. E. et al., Archives of Internal Medicine 124:663-669(1969); Slatopolsky, E., et al., Joumal of Clinical Investigation50:492-449 (1971); Bricker, N. S., New England Journal of Medicine286:1093-1099 (1972); Slatopolsky, E. S., et al., Kidney Int. 2:147-151(1972).

Antacids are often used to bind dietary phosphorus to prevent phosphorusretention and prevent its absorption. This process is referred to asphosphorus binding and appears to be a chemical reaction between dietaryphosphorus and the cation present in the binder compound, which isusually albumin or calcium. The binding results in the formation ofinsoluble and unabsorbable phosphate compounds, adsorption of phosphorusions on the surface of binder particles, or a combination of both.

Presently-used antacids are inefficient at binding phosphorus in vivo.For example, a recent study by Ramirez, et al., noted that even thoughaluminum-containing or calcium-containing antacids were administered inlarge excess, they bound only 19-35 percent of dietary phosphors.Ramirez, J. A., et al., Kidney Int. 30:753-759 (1986). Similarconclusions can be derived from data presented in earlier studies.Kirsner, J. B., Journal of Clinical Investigation, 22:47-52 (1943);Clarkson, E. M., et al., Clinical Science 43:519-531 (1972); Cam, J. M.,et al., Clinical Science and Molecular Medicine 51:407-414 (1976); Man,N. K. et al., Proceedings of the European Dialysis and TransplantationAssociation 12:245-55 (1975).

Antacids are used widely, often in large quantities, for indigestion,heartburn or peptic ulcer disease. Despite their consumption in largeamounts and often over long periods of time, phosphorus depletion isuncommon in these settings. This fact is additional evidence of theinefficiency of antacids as phosphorus binding agents.

The inefficiency of commonly used phosphorus binders creates a clinicaldilemma. The dose of the binder must be increased to controlhyperphosphatemia, but increased risk of toxicity of the binder resultsfrom the increased dose. This toxicity includes bone disease andaluminum dementia from aluminum-containing antacids and hypercalcemiaand soft tissue calcification from calcium-containing antacids. Theserisks are particularly problematic in patients with chronic renaldisease.

It would be very useful to have a phosphorus binder available which doesnot have the risks associated with ingestion of presently availablebinders. The binder should be more efficient in binding phosphorus and,thus, would not have to be consumed in the large quantities necessary,for example, when calcium carbonate-containing compositions are used.Such a phosphorus binder would be particularly valuable foradministration to individuals with chronic renal failure, in whomphosphorus retention is a serious concern and the risk of toxicity fromconsumption of presently-available binders is greater than inindividuals in whom kidney function is normal.

U.S. Pat. No. 4,870,105 addresses these concerns by disclosing a calciumacetate phosphorus binder. However, it would be advantageous to find abinder with a smaller anion and, hence, a smaller effective dose.

SUMMARY OF THE INVENTION

The present invention relates to a method of binding phosphorus in thegastrointestinal tract and, thus, reducing phosphorus absorption fromthe intestine. It also relates to a method of reducing serum phosphatelevels because phosphorus bound in the gastrointestinal tract results inlower phosphorus absorption than would otherwise occur. It isparticularly useful in the treatment and prevention of hyperphosphatemiain individuals with renal disease or other disease in which the abilityto excrete phosphorus from the body (e.g., in the urine) is impaired.

The method of the present invention comprises orally administering to anindividual a composition which includes calcium formate in sufficientquantity to effectively bind phosphorus, preferably present in food andbeverages consumed by the individual, and prevent its absorption in theintestine. In an advantageous form of the invention, the calcium formateis administered at a dose of between 0.5 and 10.0 grams.

The present invention is also a pharmaceutical composition comprisingcalcium formate in combination with a pharmaceutically acceptablecarrier. In a preferred embodiment, the composition comprises 0.5 gramsof calcium formate per capsule or tablet. In another preferredembodiment, the composition comprises calcium formate and at least oneadditional therapeutic ingredient. In a most preferred embodiment, thistherapeutic ingredient is a vitamin D compound, typicallycholecalciferol.

It is a feature of the present invention that the amount ofcalcium-containing compound sufficient to inhibit gastrointestinalphosphorus absorption is 10% lighter than therapeutically equivalentamounts of previously known calcium acetate compounds.

Other objects, features and advantages of the present invention willbecome apparent to one of skill in the art after review of thespecification and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a calcium formate composition for oraladministration to an individual. The composition is useful in reducingphosphorus absorption in the gastrointestinal tract. Calcium formate isshown below to be effective in inhibiting phosphorus absorption whenadministered orally in in vivo tests and has been shown to prevent theabsorption of ingested phosphorus at a lower dose than othercalcium-containing binders. As a result of these discoveries, calciumformate, alone or in combination with other materials, can be used tobind phosphorus in the gastrointestinal tract, thus reducing thepercentage of an amount of phosphorus consumed (i.e., of a given "dose"of phosphorus) which is absorbed. Preferably, this dose would be0.5-10.0 grams when adjusted to doses intended for human patients.

The present invention also relates to a method of inhibitinggastrointestinal phosphorus absorption. The method of the presentinvention is based on the demonstration that calcium formate is aneffective binder of phosphorus when administered orally to anindividual. The method comprises orally administering a quantity ofcalcium formate sufficient to bind with phosphorus in thegastrointestinal tract. Preferably, this dose is between 10-200milliequivalents of calcium and is preferably present in either tabletor gelatin capsule form. In a most preferable form of the presentinvention, the oral dose is ingested at mealtimes.

As a result of the present invention it is possible to administercalcium formate to reduce absorption of dietary phosphorus, which hasthe net effect of reducing the risks of adverse effects (e.g., bonedisease and secondary hyperparathyroidism) observed in individuals(e.g., chronic renal patients) in whom the ability to excrete phosphorusin the urine is impaired.

As used herein, the term "phosphorus" includes phosphorus and phosphatein its various forms (e.g. HPO₄ ⁻, PO₄ ⁻³, etc.).

According to the method of the present invention, calcium formate isadministered, alone or in combination with other substances (e.g., in ahard gelatin capsule; along with materials necessary to form a tablet orcaplet as a delivery vehicle for the calcium formate; or along with asecond phosphorus binder or other pharmaceutically useful substance) insufficient quantities to reduce phosphorus absorption in thegastrointestinal tract. The calcium formate is administered orally,preferably close in time to food and beverage consumption. By "atmealtimes" we mean within 30 minutes of a meal.

In one embodiment, 0.5-10.0 grams of anhydrous calcium formate (11-44milliequivalents calcium) is taken prior to food consumption (e.g., mealtime) and a second dose of 0.5-10.0 grams of anhydrous calcium formateis taken after food consumption. The dose or quantity to be taken at agiven time varies on an individual-by-individual basis and can beadjusted as needed (e.g., by monitoring serum concentration ofphosphorus and calcium).

The present invention is also a pharmaceutical composition comprisingcalcium formate in a pharmaceutically acceptable carrier, wherein thecalcium formate is present in an amount between 0.5-1.0 grams. Inanother embodiment, the pharmaceutical composition comprises calciumformate in amount suitable to inhibit gastrointestinal absorption ofphosphorus, provides between 11 and 44 milliequivalents of calcium, andis 10% lighter than the corresponding calcium acetate dose. By"corresponding" or "therapeutically equivalent," we mean a dose that isequally effective.

In another embodiment of the present invention, the pharmaceuticalcomposition essentially comprises only calcium formate and at least onepharmaceutically carrier, wherein the calcium formate is present in anamount sufficient to produce between 11 and 44 milliequivalents ofcalcium. By "essentially comprises" we mean that calcium formate is theonly active ingredient in the pharmaceutical composition.

The present invention is also a pharmaceutical composition comprisingcalcium formate in a pharmaceutically acceptable carrier combined withother therapeutic agents, preferably a vitamin D compound. Mostpreferably, the calcium formate is combined with vitamin D ischolecalciferol in a range of 125 IU to 400 IU in a tablet or capsule.

EXAMPLE 1

Calcium Formate as a Phosphate Binder in Normal Rats

                  TABLE 1                                                         ______________________________________                                              % Ca    Phosphorus (mg %)   Serum Ca (mg %)                             Group Formate (mean ± SEM)                                                                            Weight (mean ± SEM)                             ______________________________________                                        1 Week on Diet                                                                1     0       4.96 ± .48                                                                              209 ± 5.5                                                                         ND                                          2     1       3.25 ± .31                                                                              229 ± 5.5                                                                         ND                                          3     2       2.50 ± .32                                                                              211 ± 6.3                                                                         ND                                          4     3        2.5 ± .20                                                                              194 ± 6.5                                                                         ND                                          2 Weeks on Diet                                                               1     0       5.98 ± .39                                                                              295 ± 4.8                                                                         11.4 ± .20                               2     1       4.70 ± .62                                                                              211 ± 3.8                                                                         14.0 ± .51                               3     2        2.7 ± .24                                                                              198 ± 5.2                                                                         12.8 ± .94                               4     3        2.9 ± 0.8                                                                              150 ± 8.0                                                                         12.9 ± 1.3                               ______________________________________                                         ND = not determined. There were at least 6 rats per group.               

Five-week-old Sprague Dawley rats were given a synthetic diet containing0.47% Ca and 0.2% phosphorus for two weeks prior to the addition ofcalcium formate to the diet. Body weights were measured and blood serumwas collected after one or two weeks on calcium formate.

The results of this experiment are tabulated in Table 1. All ratssupplied with calcium formate had less serum phosphorus than controlrats. There seemed to be little difference in serum phosphorus betweenrats on 2% or 3% calcium formate thus indicating that a saturationbinding point had been reached.

I claim:
 1. A method for inhibiting gastrointestinal absorption ofphosphorous in an individual, comprising:orally ingesting a quantity ofcalcium formate sufficient to bind with phosphorous in thegastrointestinal tract.
 2. The method according to claim 1 wherein thecalcium formate is present in an amount sufficient to provide between10-200 milliequivalents of calcium.
 3. The method of claim 2 wherein thecalcium formate provides between 11 and 44 milliequivalents of calcium.4. The method according to claim 1 wherein the calcium formate is intablet form.
 5. The method according to claim 1 wherein the calciumformate is in gelatin capsule form.
 6. The method of claim 1 wherein thecalcium formate is orally ingested in a first and second dose, whereinthe first dose is before a mealtime and the second dose is after amealtime.
 7. A method for inhibiting gastrointestinal absorption ofphosphorous in an individual, comprising:orally ingesting a quantity ofcalcium formate at mealtimes.
 8. The method of claim 7 wherein thequantity of calcium formate is present in an amount sufficient toproduce between 11-44 milliequivalents of calcium.
 9. The method ofclaim 8 wherein the amount of calcium formate provides between 11 and 44milliequivalents of calcium.
 10. The method according to claim 7 whereinthe quantity of calcium formate is in tablet form.
 11. The methodaccording to claim 7 wherein the quantity of calcium formate is ingelatin capsule form.
 12. A method of reducing blood serum phosphoruslevel, comprising the step of:orally ingesting a quantity of calciumformate at mealtime sufficient to inhibit gastrointestinal absorption ofphosphorus in an individual.
 13. The method of claim 12 wherein thequantity of calcium formate is present in an amount sufficient toproduce between 10-200 milliequivalents of calcium.
 14. The methodaccording to claim 7 wherein the quantity of calcium formate is an formselected from the group consisting tablet form and gelatin capsule form.